Cysteine proteases represent a specific class of peptidases which bear a cysteine residue in the catalytic site of the enzyme. Many pathological disorders or diseases are the results of abnormal activity of cysteine proteases such as over expression or enhanced activation.
The cysteine cathepsins, e.g. cathepsins B, K, O, L, S, V and F, are a class of lysosomal protease enzymes which are implicated in a multitude of house-keeping roles, but also in various disease processes and disorders including inflammation, autoimmune diseases, e.g. rheumatoid arthritis, psoriasis, asthma, osteoarthritis, osteoporosis, tumors, coronary disease, atherosclerosis, and infectious diseases.
In contrast to the ubiquitously expressed housekeeping enzymes cathepsins B, O and L, cathepsin S (CatS) is highly expressed in antigen presenting cells of lymphatic tissues, primarily in dendritic cells, B cells and macrophages (Wiener et al., Curr. Top. Med. Chem., 2010, 10, 717). In the antigen presenting cells, CatS plays a major role in antigen presentation by degradation of invariant chain that is associated with the major histocompatibility class II complex.
There currently exists a major unmet need for safe orally administered medications for the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, chronic obstructive pulmonary disease (COPD) and cardiovascular disease, which exhibit significant damage and remodeling of extracellular matrix (ECM).
Destruction of the ECM takes place through proteolysis of its elastin, collagen and proteoglycan constituents, which provide structure, elasticity and tensile strength to materials such as cartilage, bone, lung and vascular tissue.
US 2007/0117785 discloses inhibitors of CatS, supporting the use of CatS inhibitors for the treatment of certain allergic conditions, such as rheumatoid arthritis or psoriasis.
CatS has also been demonstrated to mediate a pro-nociceptive effect, thereby indicating that endogenous CatS released by peripheral macrophages may contribute to the maintenance of neuropathic hyperalgesia following nerve injury (Barclay et al., Pain, 2007, 130, 225).
CatK is predominantly expressed in osteoclasts (Yasuda et al., Adv. Drug Deliv. Rev., 2005, 57, 973). By cleavage of bone matrix proteins, CatK is involved in extracellular matrix metabolism necessary for normal bone growth and remodelling (Bossard et al., J. Biol. Chem. 1996, 271, 12517). Hence, inhibition of CatK should result in a reduction of osteoclast mediated bone resorption. The CatK inhibitor Odanacatib has been validated in humans for the treatment of osteoporosis (Zerbini and McClung, Ther. Adv. Musculoskel. Dis. 2013, 5(4), 199-209).
The proteolytic enzymes cathepsin S and cathepsin K are up-regulated under inflammatory conditions and have been implicated in the degradation of ECM components. For instance, CatK and CatS are found over-expressed in rheumatoid and osteoarthritic synovium. They have been shown to degrade collagen type-I and type-II, as well as aggrecan (a multidomain proteoglycan component of articular cartilage) respectively (Yasuda et al., Adv. Drug Deliv. Rev., 2005, 57, 973).
Besides destruction of articular cartilage, CatS and CatK demonstrate potent elastinolytic activity and are involved in a broad spectrum of pathological conditions associated with elastin degradation, such as COPD and cardiovascular disease. Both enzymes are readily secreted by macrophages and smooth muscle cells and have been shown to degrade elastins from bovine aorta and lung tissue. CatS and CatK are also responsible for the vascular tissue damage associated with chronic cardiovascular disease and vascular injury.
Further, CatS and CatK have been found to play a crucial role in in atherosclerotic lesion destabilization and eventually induction of atherosclerotic plaque rupture (Sukhova et al., J. Clin. Invest., 1998, 102, 576). CatS and CatK have also been associated with vascular remodeling and causing ECM damage during the development of atherosclerosis and vascular injury-induced neointimal formation (Cheng et al., Am. J. Pathol., 2004, 164, 243).
Thus, inhibition of CatS and CatK offer an attractive approach to prevent the tissue destruction underlying chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, COPD and cardiovascular disease.
Since CatS and CatK appear to work in tandem and both are present in many chronic inflammatory diseases, a single compound possessing dual inhibitory activity would be a distinct advantage. There are presently no human therapeutic dual inhibitors. The use of dual CatS/K inhibitors for the treatment of conditions with inflammatory and joint-destructive components, such as rheumatoid arthritis has been suggested (Gupta et al. Expert Opin. Ther. Targets, 2008, 12, 291) and demonstrated in a collagen-induced murine arthritis model (Lee-Dutra et al., Expert Opin. Ther. Patents, 2011, 21, 311).
WO 2009/112839 A1 describes particular 6-(1S)-chlorotetrahydrofuro[3,2-b]pyrrol-3-ones according to general formula (I*), exhibiting potent dual inhibition versus both human CatS and CatK:

A major challenge in the development of such dual CatS/K inhibitors arises from selectivity issues towards other cathepsins. In particular, lysosomal, cytoskeletal and metabolic alterations in cardiomyopathy have been attributed to inhibition of cathepsin L (CatL) in CatL knock-out mice (Petermann et al., FASEB J. 2006, 20, 1266; Stypmann et al., PNAS, 2002, 99, 6234). Furthermore, it was shown that disruption of the cathepsin L gene leads to major abnormalities in skin and hair development and differentiation and alterations in trabecular bone deposition (Potts et al, Int. J. Exp. Path. 2004, 85, 85).
Structurally, the cathepsins K, L and S possess a high sequence homology (Lee-Dutra et al., Expert Opin. Ther. Patents 2011, 21, 311; Turk et al., Biochim. Biophys. Acta, 2012. 1824, 68). Therefore, a sufficient selectivity over ubiquitously expressed CatL to avoid the undesired effects associated with inhibition of CatL is regarded to be one of the prerequisites for therapeutic suitability of CatS inhibitors (Wiener et al., Curr. Top. Med. Chem. 2010, 10, 717), but will equally refer to dual CatS/CatK inhibitors.